In 2011, it was stated: ?there appears to be a strong association between the circadian system and mood regulation, although the mechanisms that underlie this association are unclear.? Our exciting preliminary data suggests that the metabotropic glutamate receptor subtype 5 (mGluR5) provides this shared mechanism, and we propose to examine this association in Major Depressive Disorder (MDD). The timing of this proposal is critical, as this highly prevalent, chronic and recurrent disorder is predicted to be the leading cause of global disease burden by the year 2030. Further, conventional MDD treatments have low success rates, potentially because MDD patients experiencing circadian rhythm impairment (which may be a significant subset, as suggested by the high rates of sleep disturbances in MDD) are not optimally treated by conventional therapeutics. Luckily, there are multiple available treatments for such impairment (chronobiotics), with repeatedly demonstrated efficacy, rapidity of action, and lack of side effects. In fact, the rapid antidepressant, ketamine, and the chronobiotic treatment, sleep deprivation, share common mechanisms, including action at mGluR5. Despite these advantageous properties, chronobiotics are significantly underutilized due to: the inability to identify those most likely to respond and a lack of understanding of circadian dysfunction and how it is corrected with treatment. Investigation of mGluR5 may provide this needed information. MGluR5 diurnal variation has been shown in vivo using Positron Emission Tomography (PET) in rodents. We were the first to observe this in humans. Further, mGluR5 dysfunction has been implicated in preclinical and clinical studies of MDD. In this innovative proposal, we take advantage of decades of circadian rhythms research that has provided an effective and feasible method of assessing circadian time. Specifically, the time between the rise of melatonin secretion levels and the midpoint of the sleep/wake cycle is referred to as the phase angle difference (PAD), and is optimally 6 hours in healthy controls. We will assess PAD in 36 MDD and 16 healthy control participants (with equal representation of each sex) to determine whether the magnitude of deviation from optimal PAD is associated with depression severity. We will also quantify mGluR5 using PET at standardized times within the circadian cycle, to confirm the mGluR5-circadian relationship and determine whether improper mGluR5 diurnal variation underlies non-optimal PAD. This will establish, for the first time, the relationship between mGluR5 expression and circadian rhythms in humans (which has implications for diseases beyond MDD and may underlie sex differences in mood and circadian regulation). Finally, we will assess the effect of sleep deprivation therapy on circadian rhythms in depressed and control individuals. This will establish which chronotypes are most amendable to treatment and whether restoration of optimal PAD is required for treatment efficacy. Regardless of outcome, this study will increase our understanding of circadian rhythms (and misalignment) in MDD as well as the mechanism of action of chronobiotic treatments.